PROJECT SUMMARY ABSTRACT Patients with coronary artery disease and type 2 diabetes mellitus are at higher risk for cardiac events than those with coronary disease but no history of diabetes. Interactions among hyperglycemia, treatment to lower blood glucose, cardiac risk factors and coronary revascularization are complex and not well delineated. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial is a multi- center randomized clinical trial that treated and followed 2368 patients with type 2 diabetes and documented coronary artery disease. The 2x2 factorial design simultaneously compared cardiac and diabetes treatment strategies: 1) prompt revascularization with intensive medical therapy versus intensive medical therapy with revascularization only when clinically indicated, and 2) an insulin sensitization versus an insulin provision approach to glycemic control, both on clinical cardiovascular outcomes. During the five- year follow-up, plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP), fibrinogen, and D-dimer were lower in the insulin sensitization group compared with the insulin provision group, indicating a lower risk of coagulation, inflammation, and thrombosis. However, neither all-cause mortality nor major cardiovascular events (composite of death, myocardial infarction and stroke) differed significantly among the randomized treatment strategy groups in the overall trial. When coronary artery bypass surgery (CABG) was pre-specified as the intended method of revascularization, prompt revascularization significantly reduced major cardiovascular events compared with initial medical therapy, and, the rate of major cardiovascular events was lowest among patients assigned to the combination of prompt revascularization and insulin sensitization. New data from core laboratory studies of adipokines are available to be analyzed with metabolic variables including HbA1c and lipids. The purpose of this application is to determine the risk of major cardiovascular events for patients with type 2 diabetes and coronary artery disease based on their multifactorial risk factor profile and treatment regimens over the course of five years of follow-up. We will create a BARI 2D Risk Score from baseline demographic, clinical, angiographic, and biochemical risk factors, obtaining a prognostic indicator of long-term risk of cardiovascular clinical outcomes. Moreover, we will evaluate how follow-up measures of the aforementioned risk factors predict death and cardiovascular events. We will test if the relationship between these risk factors and clinical outcomes depends on the randomized glycemic and cardiac treatment approaches. We hypothesize that biomarkers measured in BARI 2D, along with HbA1c level and severity of coronary disease can identify subsets of patients who will benefit from specified glycemic and cardiac treatment strategies. Such results would have important clinical implications for the treatment of the large and growing population of patients with type 2 diabetes and stable ischemic heart disease.